The compound depicted in formula I and related compounds have been reported in U.S. 4,886,814 to have utility as antidiabetics. ##STR1##
The present invention relates to novel key intermediates in the synthesis of compound I, said intermediates being (R)-4-(2-bromo-1-hydroxyethyl)-2-trifluoromethylthiazole (II) and (S)-4-oxiranyl-2-trifluoromethylthiazole (III), and to an enantioselective reduction process for the preparation of these compounds which results in their being obtained essentially free of their enantiomeric forms.
The racemic form of the bromohydrin (II), depicted below, has been reported. Within the same reference, the racemic form of the epoxide has also been reported. However, the S-bromohydrin (II) and the (S)-epoxide (III) are both previously unknown in their purified chiral forms.
It is advantageous to prepare the bromohydrin and epoxide in optically pure form since the final product of formula I has the S configuration at the hydroxyl-substituted chiral center. Therefore, a process whereby the desired stereochemistry is directly obtained is highly desirable.
The stereoselective reduction process of this invention involves the use of a borane reducing agent and a chiral oxazaborolidine catalyst. Corey, et al. (Journal of the American Chemical Society, 1987, 109, 5551-3 and 7925-6) have described generally the reduction of a limited number of ketones with boranes utilizing chiral oxazaborolidines to elicit enantioselectivity. However, recent studies by Jones, et al. (Journal of Organic Chemistry, 1991, 56, 763-9) have demonstrated that the method loses its effectiveness when molecules possessing borane coordination sites are present in the reaction mixture. Examples of compounds containing borane coordination sites include but are not limited to such compounds as boronic acids, boroxines, prolinols, amines, thiazoles and oxazoles. This loss of effectiveness is manifested in diminished enantioselectivity. The present invention is directed to a process in which the deleterious effect of said borane coordination sites has been overcome.